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Exercise Training & Mental Health

Exercise Training & Mental Health

Exercise training impacts skeletal muscle gene expression related to the kynurenine pathway

Exercise positively impacts mood and symptoms of depression; however, the mechanisms underlying these effects are not fully understood. Recent evidence highlights a potential role for skeletal muscle-derived transcription factors to influence tryptophan metabolism, along the kynurenine pathway, which has important implications for depression. This has important consequences for older adults, whose age-related muscle deterioration may influence this pathway and may increase their risk for depression.


Although exercise training has been shown to improve skeletal muscle mass in older adults, whether this also translates into improvements in transcription factors and metabolites related to the kynurenine pathway has yet to be examined. The aim of the present study was to examine the influence of a 12-wk exercise program on skeletal muscle gene expression of transcription factors, kynurenine aminotransferase (KAT) gene expression, and plasma concentrations of tryptophan metabolites (kynurenines) in healthy older men over 65 yr of age.


Exercise training significantly increased skeletal muscle gene expression of transcription factors (peroxisome proliferator-activated receptor-γ coactivator 1α, peroxisome proliferator-activated receptor-α, and peroxisome proliferator-activated receptor-δ: 1.77, 1.99, 2.18-fold increases, respectively, P < 0.01] and KAT isoforms 1–4 (6.5, 2.1, 2.2, and 2.6-fold increases, respectively, P ≤ 0.01). Concentrations of plasma kynurenines were not altered. These results demonstrate that 12 wk of exercise training significantly altered skeletal muscle gene expression of transcription factors and gene expression related to the kynurenine pathway, but not circulating kynurenine metabolites in older men.


These findings warrant future research to determine whether distinct exercise modalities or varying intensities could induce a shift in the kynurenine pathway in depressed older adults.

According to the World Health Organization, depression is the single largest contributor to global disability. A disproportionately large number of those suffering are older adults, whose disability due to depression is augmented by age-related declines in their physical health and mobility. Traditional pharmaceuticals used in the treatment of depression (i.e., selective serotonin reuptake inhibitors) are often ineffective at reducing primary symptoms; these drugs are also associated with adverse side effects and high rates of relapse. Exercise may be a beneficial alternative or adjunctive treatment strategy to the pharmaceutical treatment of depression. In addition to its positive effects on physical health and mobility in aging, exercise can reduce symptoms of depression. However, the mechanisms underlying these effects are not fully understood, and this information is critical for determining the effectiveness of exercise as a treatment strategy for depression in older adults.


Preliminary research in younger adults suggests that skeletal muscle may play an important role in the mood-enhancing effects of exercise. Specifically, exercise upregulates the expression of skeletal muscle-derived transcription factors that are responsible for promoting the expression of key enzymes that influence tryptophan (Trp) metabolism. Importantly, Trp is the precursor for serotonin (5-HT) synthesis, and alterations in Trp metabolism may contribute to the low central 5-HT concentrations observed in major depressive disorder (MDD). Approximately 95% of Trp metabolism occurs via the kynurenine (KYN) pathway. Trp is first degraded into the metabolite KYN. This metabolite is capable of crossing the blood-brain barrier (BBB) and can therefore undergo further metabolism peripherally as well as within the brain. KYN is metabolized along one of two distinct branches of the kynurenine pathway: a neuroprotective branch and a neurotoxic branch. The neuroprotective branch depends on the enzyme kynurenine aminotransferase (KAT), which results in the production of the non-BBB transportable metabolite kynurenic acid (KYNA). In contrast, the neurotoxic branch depends on the enzyme kynurenine monooxygenase (KMO), which shifts the pathway towards the production of potentially neurotoxic metabolites, including 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN).


Both aerobic and resistance exercise training may bias the metabolism of Trp towards the neuroprotective branch by increasing KAT activity. Specifically, skeletal muscle-derived transcriptional coactivators, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptor-α (PPARα), and peroxisome proliferator-activated receptor-δ (PPARδ), promote KAT expression. Furthermore, skeletal muscle PGC-1α overexpression is associated with a protective shift in Trp metabolism in animal models. One prior study in younger adults demonstrated that aerobic exercise training can induce a protective shift in the kynurenine pathway related to increases in skeletal muscle transcription factors. Although this has yet to be examined in older adults, previous research has shown that, in rodents, aging is accompanied by a loss of exercise-induced expression of skeletal muscle PGC-1α. If older humans demonstrate a similar loss it may negatively impact the potential for exercise to influence the kynurenine pathway and ultimately impair the mood-enhancing properties of physical activity.


The present study examined whether, in a group of healthy, non-depressed older men, a 12-wk combined (resistance + high-intensity interval training) exercise training program would enhance skeletal muscle gene expression of transcriptional coactivators and bias the kynurenine pathway towards the neuroprotective branch. We hypothesized that the exercise training program would increase skeletal muscle gene expression of PGC-1α, PPARα, and PPARδ, which would relate to an increase in KAT gene expression and a decrease in the ratio of QUIN-to-KYNA plasma metabolites, indicating a shift in the kynurenine pathway towards the neuroprotective branch.

David J. Allison, Joshua P. Nederveen, Tim Snijders, Kirsten E. Bell, Dinesh Kumbhare, Stuart M. Phillips, Gianni Parise, Jennifer Heisz. Exercise training impacts skeletal muscle gene expression related to the kynurenine pathwayAmerican Journal of Physiology-Cell Physiology, 2019; DOI: 10.1152/ajpcell.00448.2018
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